PROJECT SUMMARY/ABSTRACT A myriad of human mucosal diseases are intimately connected with the ecology of the flora residing at disease sites. The etiology of these complex polymicrobial diseases is poorly described by Koch's Postulates and the key mechanisms of polymicrobial pathogenesis are still emerging in the field. The limited utility of traditional antibiotic therapies as well as our inadequate understanding of polymicrobial disease etiology are both currently significant hurdles for the effective treatment of these diseases. The thematic basis for the current proposal is to utilize genetically tractable members of the oral flora as a model system to investigate the mechanistic and regulatory foundations of polymicrobial synergy as well as potential mechanisms to counteract synergistic pathogenesis in these types of diseases. The proposed research program will consist of 3 conceptually complementary research foci: 1) the genetic control of virulence, 2) mechanisms of polymicrobial synergy, and 3) novel strategies for targeted inhibition of bacteria. Success in each of these focus areas will be leveraged by our established strengths in oral bacterial genetics and the application of a state-of-the-art genetic system. We are proposing to further develop Streptococcus mutans as a preeminent model organism for genetic studies of flora pathobiology, while also developing a new model system of polymicrobial synergy using abscess clinical isolates of Anginosus group streptococci in combination with abscess clinical isolates of Fusobacterium spp. and Prevotella spp. The Anginosus streptococci are vastly understudied members of the oral flora strongly associated with the formation of severe polymicrobial abscesses in the oral cavity and throughout the body. Such abscesses are surprisingly common, yet little is known about the pathogenic mechanisms involved, other than the essential role of polymicrobial synergy, especially with Fusobacterium and Prevotella species. Thus, we envision utilizing the long-term support provided by the R35 mechanism to both augment our existing programmatic strengths and also to grow our research program in an understudied area of major clinical significance.